Human obesity is a recognized health problem with approximately 97 million people considered clinically overweight in the United States. The accumulation or maintenance of body fat bears a direct relationship to caloric intake. Therefore, one of the most common methods for weight control to combat obesity is the use of relatively low-fat, low calorie diets, that is, diets containing less fat and calories than a xe2x80x9cnormal dietxe2x80x9d or that amount generally consumed by the patient.
The presence of fats in a great many food sources greatly limits the food sources which can be used in a low-fat diet. Additionally, fats contribute to the flavor, appearance and physical characteristics of many foodstuffs. As such, the acceptability of low-fat diets and the maintenance of such diets are difficult. Various chemical approaches have been proposed for controlling obesity. Anorectic agents, such as dextroamphetamine, the combination of the non-amphetamine drugs phentermine and fenfluramine (xe2x80x9cPhen-Fenxe2x80x9d) and dexfenfluramine (Redux) alone, are associated with serious side effects. Indigestible materials such as OLESTRA(trademark), mineral oil or neopentyl esters (see U.S. Pat. No. 2,962,419) have been proposed as substitutes for dietary fat. Garcinia acid and derivatives thereof have been described as treating obesity by interfering with fatty acid synthesis. Swellable crosslinked vinyl pyridine resins have been described as appetite suppressants via the mechanism of providing non-nutritive bulk, as in U.S. Pat. No. 2,923,662. Surgical techniques, such as temporary ideal bypass surgery, are employed in extreme cases.
However, methods for treating obesity, such as those described above, have serious shortcomings with controlled diet remaining the most prevalent technique for controlling obesity. As such, new methods for treating obesity are needed.
The present invention relates to a method for treating obesity, a method for reducing the absorption of dietary fat, and a method for treating hypertriglyceridemia in a patient and to particular polymers for use in the methods or in a manufacture of a medicament. The methods comprise the step of orally administering to a mammal, such as a human, a therapeutically effective amount of a fat-binding polymer. The administration of a fat-binding polymer of the invention facilitates the excretion of fat from the body without digestion, with minimal side effects and low toxicity. In a preferred embodiment, the fat-binding polymers are administered in combination with a therapeutically effective amount of a lipase inhibitor, such as the pancreatic lipase inhibitors described in U.S. Pat. No. 4,598,089 to Hadvary et al. The combination administration can reduce undesirable side effects often encountered when lipase inhibitors, in particular, the pancreatic lipase inhibitors lipstatin and tetrahydrolipstatin are administered alone. For example, a serious side effect resulting from the administration of a lipase inhibitor is steatorrhea, or fatty stools.
The fat-binding polymers of the invention comprise at least one fat-binding region. A fat-binding region can include a region having a positive charge, a region which is hydrophobic or a region having a positive charge and which is hydrophobic.
In one embodiment, the fat-binding polymer is an aliphatic polymer selected from the group consisting of polyalkylacrylates, polyacrylamides, polyalkylmethacrylates, polymethacrylamides, poly-N-alkylacrylamides, poly-N-alkylmethacrylamides, substituted derivatives thereof and copolymers thereof. For example, the substituted derivatives of the polymers can be characterized by one or more substituents, such as substituted or unsubstituted, saturated or unsaturated alkyl, and substituted or unsubstituted aryl groups. Suitable substituents to employ on the alkyl or aryl groups include, but are not limited to, cationic or neutral groups, such as alkoxy, aryl, aryloxy, aralkyl, halogen, amine, and ammonium groups. For example, the polymer can be poly(dimethylamino propylacrylamide), poly(trimethylammonium ethylacrylate), poly(trimethylammonium ethyl methacrylate), poly(trimethylammonium propyl acrylamide), poly(dodecyl acrylate), poly(octadecyl acrylate), poly(octadecyl methacrylate) and copolymers thereof.
In another embodiment, the fat binding polymer is a synthetic amine polymer and pharmaceutically acceptable salts thereof. Amine polymers (or salts thereof) suitable for use in the invention include, but are not limited to, substitued or unsubstituted polymers or copolymers of the following monomers: allylamine, diallyldimethyl ammonium, ethyleneimine, vinylamine, diallylamine, vinylimidazole and diallylmethylamine.
In another embodiment, the fat binding polymer is an amine derivative of an anhydride containing polymer.
In yet another embodiment, the fat-binding polymer is a hydroxyl-containing polymer, for example, poly(vinylalcohol).
In a specific embodiment, the fat-binding polymer is an amine-containing polymer wherein one or more hydrophobic regions are bound to a portion of the amine nitrogens of the amine polymer. In a particular embodiment, between about 1 and about 60 percent of the amine nitrogens are substituted, preferably between about 1 and about 30 percent.
In another embodiment, the hydrophobic region of the fat-binding polymer can include a hydrophobic moiety, for example, a substituted or unsubstituted, normal, branched or cyclic alkyl group having at least four carbons. In a particular embodiment, the hydrophobic moiety is an alkyl group of between about four and thirty carbons.
In another embodiment, the hydrophobic region is a quaternary amine-containing moiety having a terminal hydrophobic substituent. Suitable hydrophobic regions which can include a hydrophobic moiety and/or a quaternary amine-containing moiety are described herein and in U.S. Pat. Nos. 5,607,669, 5,679,717 and 5,618,530, the entire contents of which are incorporated herein by reference in their entirety.
The polymers of the present invention offer desirable pharmacological properties such as excellent fat binding properties and low toxicity. In addition, when the fat-binding polymers are administered in combination with lipase inhibitors, as described herein, undesirable side effects experienced, such as steatorrhea, when the lipase inhibitors are administered alone can be lessened.
The features and other details of the invention will now be more particularly described and pointed out below as well as in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention.
In one aspect, the invention relates to a method for treating obesity comprising the step of orally administering to a mammal a therapeutically effective amount of one or more fat-binding polymers. In a preferred embodiment, the fat-binding polymer is administered in combination with a therapeutically effective amount of a lipase inhibitor.
In another aspect, the invention relates to a method for reducing the absorption of dietary fat comprising the step of orally administering to a mammal a therapeutically effective amount of one or more fat-binding polymers. In a preferred embodiment, the fat-binding polymer is administered in combination with a therapeutically effective amount of a lipase inhibitor.
In yet another aspect, the invention relates to a method for treating hypertriglyceridemia in a mammal comprising the step of orally administering to a mammal a therapeutically effective amount of one or more fat-binding polymers. In a preferred embodiment, the fat-binding polymer is administered in combination with a therapeutically effective amount of a lipase inhibitor.
A particular aspect of the invention relates to a method for treating steatorrhea comprising the step of orally administering to a mammal a therapeutically effective amount of a fat-binding polymer. In a specific embodiment, the steatorrhea is a result of the administration of a lipase inhibitor.
The invention also relates to fat-binding polymers useful in the method of the invention.
xe2x80x9cLipasesxe2x80x9d as that term is used herein, are ubiquitous enzymes which hydrolyze ester bonds in neutral lipids. Examples of lipases include, but are not limited to, pancreatic and gastric lipases. The preferred substrates of lipases are insoluble in water. Lipases exhibit maximal activity in the presence of lipid/water interfaces. For example, pancreatic lipase, which is the key enzyme of dietary triglyceride absorption, exerts it activity at the water/lipid interface, in conjunction with bile salts and co-lipase.
xe2x80x9cLipase inhibitorxe2x80x9d as that term is used herein refers to compounds which are capable of inhibiting the action of lipases, for example, gastric and pancreatic lipases. Lipstatin and its tetrahydro derivative, Tetrahydrolipstatin, as described in U.S. Pat. No. 4,598,089 to Hadvary et al., the entire content of which is hereby incorporated by reference, are potent inhibitors of both gastric and pancreatic lipases, as well as cholesterol ester hydrolase. Lipstatin is a natural product of microbial origin, and tetrahydrolipstatin is the result of catalytic hydrogenation of lipstatin. Other lipase inhibitors include a class of compound commonly referred to as Panclicins. Panclicins are analogues of Tetrahydrolipstatin (See e.g., Mutoh, M., et al., xe2x80x9cPanclicins, Novel Pancreatic Lipase Inhibitors, II. Structural Elucidation,xe2x80x9d The Journal of Antibiotics, 47(12): 1376-1384 (1994), the entire content of which is hereby incorporated by reference.)
xe2x80x9cFat-binding polymersxe2x80x9d, as that term is used herein, are polymers which absorb, bind or otherwise associate with fat thereby inhibiting (partially or completely) fat digestion, hydrolysis, or absorption in the gastrointestinal tract and/or facilitate the removal of fat from the body prior to digestion. The fat-binding polymers comprise one or more fat-binding regions. xe2x80x9cFat-binding regionsxe2x80x9d, as defined herein can include a positively charged region, a hydrophobic region, or a region which is both positively charged and hydrophobic.
xe2x80x9cFatsxe2x80x9d, as that term is used herein, are solids or liquid oils generally consisting of glycerol esters of fatty acids. Sources of fats include both animal and vegetable fats, for example, triglyceride esters of saturated and/or unsaturated fatty acids, free fatty acids, diglycerides, monoglycerides, phospholipids and cholesterol esters are fats, as defined herein.
A variety of polymers can be employed in the invention described herein. The polymers are synthetic polymers which can be aliphatic, or aromatic. However, aliphatic and synthetic polymers are preferred. A xe2x80x9csynthetic polymerxe2x80x9d, as that term is employed herein, is a polymer which is not obtainable from a natural source either directly or through a minor derivatization of the naturally occurring form. Further, the polymer can be hydrophobic, hydrophilic or copolymers of hydrophobic and/or hydrophilic monomers. Particularly preferred polymers comprise monomers having both cationic and hydroxy functional groups, and/or comprise a combination of separate monomers each having either a cationic or hydroxy functional group. Other preferred polymers comprise monomers having both cationic and hydrophobic groups, and/or comprise a combination of separate monomers each having either a cationic or a hydrophobic functional groups. As used herein the term xe2x80x9ccombination of monomersxe2x80x9d or xe2x80x9ccombination of repeat unitsxe2x80x9d means that at least one of each monomer or at least one of each repeat unit are present in the resulting polymerized polymer in any order. Many polymers can be conveniently manufactured from olefinic or ethylenic monomers (such as vinylalcohol, allylamine or acrylic acid) or condensation polymers. Examples of the preparation of preferred polymers of the invention are included in Examples 1-98.
For example, the polymers can include substituted or unsubstituted polyvinylalcohol, polyvinylamine, poly-N-alkylvinylamine, polyallylamine, poly-N-alkylallylamine, polydiallylamine, poly-N-alkyldiallylamine, polyalkylenimine, other polyamines, polyethers, polyamides, polyacrylic acids, polyalkylacrylates, polyacrylamides, polymethacrylic acids, polyalkylmethacrylates, polymethacrylamides, poly-N-alkylacrylamides, poly-N-alkylmethacrylamides, polystyrene, polyvinylnaphthalene, polyethylvinylbenzene, polyaminostyrene, polyvinylbiphenyl, polyvinylanisole, polyvinylimidazolyl, polyvinylpyridinyl, polydimethylaminomethylstyrene, polydiallylmethylammonium chloride, polytrimethylammonium ethyl methacrylate, polytrimethylammonium ethyl acrylate, and copolymers thereof. In addition, the polymers can be further characterized by one or more substituents such as substituted and unsubstituted, saturated or unsaturated alkyl, and substituted or unsubstituted aryl groups. Suitable groups to employ include cationic or neutral groups, such as alkoxy, aryl, aryloxy, aralkyl, halogen, amine, ammonium groups, substituted or unsubstituted oxypolyethylene oxide, and mono, di or higher hydroxyalkyl groups.
Particularly preferred polymers (or salts thereof) include substituted or unsubstituted polydiethylammonium chloride, polyvinylimidazole, polyalkylacrylates, polyacrylamides, polyalkylmethacrylates, polymethacrylamides, poly-N-alkylacrylamides, poly-N-alkylmethacrylamides and copolymers thereof. These polymers can be further characterized by one or more substituents such as those discussed above.
Other particularly preferred polymers include aliphatic amine polymers, such as polyallylamine, polydiallylamine, polydiallylmethylamine, polyvinylamine, polyethylenimine. In a specific embodiment, the amine polymer comprises one or more hydrophobic regions which are bound to a portion of the amine nitrogens of the amine polymer. In a particular embodiment, between about 1 and about 60 percent of the amine nitrogens are substituted, preferably between about 1 and about 30 percent.
Additional particularly preferred polymers include maleic anhydride and maleic anhydride olefinic copolymers, itaconic anhydride, and amine derivatives thereof. The amine derivatives may preferably contain dimethyl amino groups.
In one embodiment, the hydrophobic region of the fat-binding polymer can include a hydrophobic moiety, for example, a substituted or unsubstituted, normal, branched or cyclic alkyl group having at least four carbons. In a specific embodiment, the hydrophobic moiety is an alkyl group of between about four and thirty carbons.
In another embodiment, the hydrophobic region is a quaternary amine-containing moiety having a terminal hydrophobic substituent.
In yet another embodiment, the fat-binding region comprises a nitrogen, for example, the nitrogen of an amine, capable of possessing a positive charge under conditions present in the gastro-intestinal tract. For example, a quaternary amine-containing moiety, or the nitrogen of a polyamine.
In yet another embodiment, the fat-binding polymer is a hydroxyl-containing polymer, for example, poly(vinylalcohol) which can comprise further fat-binding regions. For example, the polymer comprises a repeat unit having the formula 
wherein R is a hydrophobic region.
Preferred polymers are copolymers that comprise both cationic monomers such as those containing nitrogen, and monomers with hydroxy groups.
Other polymers and methods of preparation, which can be used in the claimed invention have been reported in the patent literature in, for example, U.S. Pat. Nos. 5,487,888, 5,496,545, 5,607,669, 5,618,530, 5,624,963, 5,667,775, and 5,679,717 and co-pending U.S. Applications having Ser. Nos. 08/471,747, 08/482,969, 08/567,933, 08/659,264, 08/823,699, 08/835,857, 08/470,940, 08/461,298, 08/826,197, 08/777,408, 08/927,247, 08/964,956, 08/964,498, and 08/964,536, the entire contents of all of which are incorporated herein by reference.
The polymer can be linear or crosslinked. Crosslinking can be performed by reacting the copolymer with one or more crosslinking agents having two or more functional groups, such as electrophilic groups, which react with, for example, amine groups to form a covalent bond. Crosslinking in this case can occur, for example, via nucleophilic attack of the polymer amino groups on the electrophilic groups. This results in the formation of a bridging unit which links two or more amino nitrogen atoms from different polymer strands. Suitable crosslinking agents of this type include compounds having two or more groups selected from among acyl chloride, epoxide, and alkyl-X, wherein X is a suitable leaving group, such as a halo, tosyl or mesyl group. Examples of such compounds include, but are not limited to, epichlorohydrin, succinyl dichloride, acryloyl chloride, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, pyromellitic dianhydride, and dihaloalkanes. These crosslinking agents are referred to herein as multifunctional crosslinking agents.
The polymer composition can also be crosslinked by including a multifunctional co-monomer as the crosslinking agent in the polymerization reaction mixture. A multifunctional co-monomer can be incorporated into two or more growing polymer chains, thereby crosslinking the chains. Suitable multifunctional co-monomers include, but are not limited to, diacrylates, triacrylates, and tetraacrylates, dimethacrylates, diacrylamides, and dimethacrylamides. Specific examples include ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis(methacrylamide), ethylene bis(acrylamide), ethylene bis(methacrylamide), ethylidene bis(acrylamide), ethylidene bis(methacrylamide), pentaerythritol tetraacrylate, trimethylolpropane triacrylate, bisphenol A dimethacrylate, and bisphenol A diacrylate. Other suitable multifunctional monomers include polyvinylarenes, such as divinylbenzene.
The amount of cross-linking agent is typically between about 0.01 and about 10 weight % based on the combined weight of crosslinking agent and monomers, with 0.1-3% being preferred. Typically, the amount of cross-linking agent that is reacted with the polymer, when the crosslinking agent is a multifunctional agent, is sufficient to cause between about 0.1 and 6 percent of the nucleophiles present on the monomer, for example, an amine to react with the crosslinking agent.
The hydrophobic region or regions of the fat-binding polymers include but are not limited to, for example, a hydrophobic moiety such as a substituted or unsubstituted, normal, branched or cyclic alkyl group having at least about four carbons and preferably at least 6 carbons. For example, a hydrophobic moiety such as an alkyl group of at least four carbons and preferably at least 6 carbons can be bound to the fat-binding polymer, for example, through an amine of the fat-binding polymer.
A xe2x80x9chydrophobic moiety (group)xe2x80x9d, as the term is used herein, is a moiety which, as a separate entity, is more soluble in octanol than water. For example, the octyl group (C8H17) is hydrophobic because its parent alkane, octane, has greater solubility in octanol than in water. The hydrophobic moieties can be a saturated or unsaturated, substituted or unsubstituted hydrocarbon group. Such groups include substituted and unsubstituted, normal, branched or cyclic alkyl groups having at least four carbon atoms, substituted or unsubstituted arylalkyl or heteroarylalkyl groups and substituted or unsubstituted aryl or heteroaryl groups. Preferably, the hydrophobic moiety includes an alkyl group of between about four and thirty carbons. Specific examples of suitable hydrophobic moieties include the following alkyl groups n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-octadecyl, 2-ethylhexyl, 3-propyl-6-methyl decyl, phenyl and combinations thereof. Other examples of suitable hydrophobic moieties include haloalkyl groups of at least six carbons (e.g., 10-halodecyl), hydroxyalkyl groups of at least six carbons (e.g., 11-hydroxyundecyl), and aralkyl groups (e.g., benzyl).
The positively charged region or regions of the fat binding polymers may include primary, secondary, tertiary or quaternary amines. Optionally, the positively charged region or regions of the fat-binding polymers may include an amine nitrogen capable of possessing a positive charge under conditions present in the gastro-intestinal tract and a quaternary amine-containing moiety. Suitable quaternary amine-containing moieties used in conjunction with acrylate or acrylamide polymers, for example, include alkyl trialkylammonium groups also referred to as ammonioalkyl groups. The term, xe2x80x9cammonioalkylxe2x80x9d, as used herein, refers to an alkyl group which is substituted by a nitrogen bearing three additional substituents. Thus, the nitrogen atom is an ammonium nitrogen atom which bears an alkylene substituent, which links the ammonium nitrogen atom to the polymer, and three additional terminal alkyl substituents having from about one to about twenty-four carbons. A xe2x80x9cterminal substituentxe2x80x9d of the quaternary amine-containing moiety, as the term is employed herein, is any one of the three substituents on the quaternary amine nitrogen. In a specific embodiment, the polymer is an amine polymer and the alkylene group links the ammonium nitrogen atom to the nitrogen atom of the polymer. It is to be understood that multiple moieties can be bound to the same amine and/or different amines of the polymer composition.
In another embodiment, the quaternary amine-containing moiety can bear at least one terminal hydrophobic alkyl substituent, such as an alkyl group having between about four and twenty-four carbons, thereby providing both a hydrophobic region and a positively charged region in combination.
An ammonioalkyl group will further include a negatively charged counterion, such as a conjugate base of a pharmaceutically acceptable acid. Examples of suitable counterions include Clxe2x88x92, PO4xe2x88x92, Brxe2x88x92, CH3SO3xe2x88x92, HSO4xe2x88x92, SO42xe2x88x92, HCO3xe2x88x92, CO32xe2x88x92, acetate, lactate, succinate, propionate, butyrate, ascorbate, citrate, maleate, folate, tartrate, polyacrylate, an amino acid derivative, and a nucleotide.
Suitable ammonioalkyl groups are of the general formula: 
wherein, R1, R2 and R3 represent an alkyl group, wherein each R1-R3, independently, is a normal or branched, substituted or unsubstituted alkyl group having a carbon atom chain length of between about one to about twenty-four carbon atoms, n is an integer having a value of two or more and Y is a negatively charged counterion. In a particular embodiment, R1, R2 and R3 are all methyl groups and n is an integer between about 2 and about 12. Examples of preferred alkylene linking groups are ethyl, propyl, butyl, pentyl, hexyl, octyl, and decyl groups. Example of suitable quaternary amine-containing moieties include, but are not limited to:
3-(trimethylammonio)propyl;
4-(trimethylammonio)butyl;
6-(trimethylammonio)hexyl;
8-(trimethylammonio)octyl;
10-(trimethylammonio)decyl;
12-(trimethylammonio)dodecyl and combinations thereof. A particularly preferred amine-containing moiety is a 6-(trimethylammonio)hexyl group.
Alternatively, a quaternary amine-containing moiety and a hydrophobic moiety are present in the same substituent, thereby providing both a positively charged and hydrophobic region in combination. For example, the quaternary amine nitrogen or ammonium nitrogen of the quaternary amine-containing moiety is bound to the polymer backbone by an alkylene having two or more carbons. However, at least one of the three terminal substituents (R1, R2 and R3) of the ammonium nitrogen is a hydrophobic alkyl group having from four to about twenty-four carbons. The remaining terminal substituents are each independently a normal or branched, substituted or unsubstituted alkyl group having from one to about twenty-four carbons or a hydrogen atom. In another embodiment, at least two of the three terminal substituents can be hydrophobic alkyl groups having from four to about twenty-four carbons, the remainder having from one to about twenty-four carbons or a hydrogen atom. In a further embodiment, all three of the terminal substituents can be hydrophobic alkyl groups having from six to about twenty-four carbons.
A xe2x80x9chydrophobic alkyl groupxe2x80x9d, as that term is employed herein, includes a substituted or unsubstituted alkyl group having from four to about twenty-four carbons and which is hydrophobic, as earlier defined. The hydrophobic alkyl group can be, for example, a normal or branched, substituted or unsubstituted alkyl group having from six to about twenty-four carbons.
Particular examples of quaternary amine-containing moieties, which provide both a hydrophobic and quaternary amine-containing substituent, include, but are not limited to:
4-(dioctylmethylammonio)butyl;
3-(dodecyldimethylammonio)propyl;
3-(octyldimethylammonio)propyl;
3-(decyldimethylammonio)propyl;
5-(dodecyldimethylammonio)pentyl;
6-(dimethyldecylammonio)hexyl;
6-(decyldimethylammonio)hexyl;
3-(tridecylammonio)propyl;
3-(docosyldimethylammonio)propyl;
6-(docosyldimethylammonio)hexyl;
4-(dodecyldimethylammonio)butyl;
3-(octadecyldimethylammmonio)propyl;
3-(hexyldimethylammonio)propyl;
3-(methyldioctylammonio)propyl;
3-(didecylmethylammonio)propyl;
3-(heptyldimethylammonio)propyl;
3-(dimethylnonylammonio)propyl;
6-(dimethylundecylammonio)hexyl;
4-(heptyldimethylammonio)butyl;
4-(dioctylmethylammonio)butyl;
6-(octyldimethylammonio)hexyl;
12-(decyldimethylammonio)dodecyl;
3-(dimethylundecylammonio)propyl; and
3-(tetradecyldimethylammonio)propyl.
Other suitable quaternary amine-containing moieties include secondary and tertiary analogs, such as 4-(dioctylmethylammonio)4-methylbutyl and 4-(dioctylmethylammonio)-4,4-dimethylbutyl.
The fat-binding polymers of the invention can be formed, for example, by reacting a polymer, which can be linear or crosslinked, with a suitable alkylating agent or by polymerizing an alkylated monomer.
An xe2x80x9calkylating agentxe2x80x9d, as that term is employed herein, means a reactant that, when reacted with a monomer or a copolymer characterized by a repeat unit of the invention and having a nucleophilic site capable of reaction with the alkylating agent, causes a hydrophobic substituent, as described herein, to be covalently bound to one or more of sites on the fat-binding polymer, for example, the amine nitrogen atoms or hydroxyl oxygens of an amine-containing or hydroxyl-containing monomer or polymer, respectively. Further, when multiple substituents are employed, they can be bound to the same and/or different nucleophilic sites of the fat-binding polymer, for example, the same and/or different amine nitrogens of an amine-containing fat-binding polymer or hydroxyl oxygen of a hydroxyl-containing polymer.
Suitable alkylating agents are compounds comprising an alkyl group or alkyl derivative, having at least four carbon atoms, which is bonded to a leaving group such as a halo (e.g., chloro, bromo or iodo), tosylate, mesylate or epoxy group).
Examples of suitable alkylating agents which provide a hydrophobic moiety include alkyl halides having at least four carbon atoms, such as n-hexyl halide, n-heptyl halide, n-octyl halide, n-nonyl halide, n-decyl halide, n-undecyl halide, n-dodecyl halide, n-tetradecyl halide, n-octadecyl halide, and combinations thereof. Other examples include: a dihaloalkane that includes an alkyl group of at least four carbons (e.g., a 1,10-dihalodecane); a hydroxyalkyl halide having at least four carbon atoms (e.g., an 11-halo-1-undecanol); an aralkyl halide (e.g., a benzyl halide); an alkyl epoxy ammonium salt having at least six carbons (e.g., glycidylpropyl-trimethylammonium salts) and epoxyalkylamides having at least six carbons (e.g., N-(2,3-epoxypropyl)butylamine or N-(2,3-epoxypropyl)hexanamide). Preferred halogen components of the alkyl halides are bromine and chlorine. Particularly preferred alkylating agents which, when reacted with the polymer composition, will cause formation of an amine polymer reaction product that includes a first substituent, are 1-bromodecane and 1-chlorooctane.
Examples of suitable alkylating agents which can provide a quaternary amine-containing moiety have the general formula: 
wherein,
R1, R2, and R3 represent an alkyl group, wherein each R independently is a normal or branched, substituted or unsubstituted alkyl group having a carbon atom chain length of between about one to about twenty four carbon atoms,
n is an integer having a value of two or more,
X is a leaving group as earlier described, and
Y is a negatively charged counterion.
When at least one of the three terminal substituents of the quaternary amine alkylating agent is a hydrophobic alkyl group having from four to about twenty-four carbons, the alkylating agent therefore provides both a hydrophobic moiety and a quaternary amine-containing moiety. The alkylene group in this instance is three or more carbon atoms in length.
Particular examples of quaternary ammonium compounds suitable as alkylating agents include the following:
(4-bromobutyl)dioctylmethylammonium bromide;
(3-bromopropyl)dodecyldimethylammonium bromide;
(3-chloropropyl)dodecyldimethylammonium bromide;
(3-chloropropyl)decyldimethylammonium bromide;
(5-tosylpentyl)dodecyldimethylammonium bromide;
(6-bromohexyl)dimethyldecylammonium bromide;
(12-bromododecyl)decyldimethylammonium bromide;
(3-bromopropyl)tridecylammonium bromide;
(3-bromopropyl)docosyldimethylammonium bromide;
(6-bromohexyl)docosyldimethylammonium bromide;
(4-chlorobutyl)dodecyldimethylammonium bromide;
(3-chloropropyl)octadecyldimethylammonium bromide;
(3-bromopropyl)octyldimethylammonium bromide;
(4-iodobutyl)dioctylmethylammonium bromide;
(2,3-epoxy propyl)decyldimethylammonium bromide; and
(6-bromohexyl)docosyldimethyammonium bromide.
Other suitable alkylating agents include secondary and tertiary analogs, such as (3-bromobutyl)dioctylmethylammonium bromide and (3-chloro-3,3-dimethyl propyl)dioctylmethylammonium bromide.
Examples of suitable alkyl trimethylammonium alkylating agents include alkyl halide trimethylammonium salts, such as:
(4-halobutyl)trimethylammonium salt;
(5-halopentyl)trimethylammonium salt;
(6-halohexyl)trimethylammonium salt;
(7-haloheptyl)trimethylammonium salt;
(8-halooctyl)trimethylammonium salt;
(9-halononyl)trimethylammonium salt;
(10-halodecyl)trimethylammonium salt;
(11-haloundecyl)trimethylammonium salt;
(12-halododecyl)trimethylammonium salt; and combinations thereof A particularly preferred quaternary amine-containing alkylating agent is (6-bromohexyl)-trimethylammonium bromide.
The fat-binding polymers of the invention can be formed, for example, by reacting a polymer, which can be linear or crosslinked, with a suitable modifying agent. A xe2x80x9cmodifying agentxe2x80x9d, as that term is employed herein, means a reactant that, when reacted with a monomer or a copolymer characterized by a repeat unit of the invention and having a nucleophilic site capable of reaction with the modifying agent, causes a hydrophobic substituent, as described herein, to be covalently bound to one or more of sites on the fat-binding polymer, for example, the amine nitrogen atoms of an amine-containing polymer. Further, when multiple substituents are employed, they can be bound to the same and/or different nucleophilic sites of the fat-binding polymer, for example, the same and/or different amine nitrogens of an amine-containing fat-binding polymer.
Suitable modifying agents are compounds comprising substituted alkyl group or alkyl aromatic groups which is bonded to a leaving group such as a halo (e.g., chloro, bromo or iodo), tosylate, mesylate or epoxy group). Examples of suitable modifying agents which provide a hydrophilic moiety include haloalkanols, (for example, 2-bromoethanol, 3-bromopropanol, 4-bromobutanol, 4-chlorobutanol and 3-bromo-2-hydroxy propanol), haloalkanoic acids (for example chloroacetic acid, bromoacetic acid, 3-bromo propionic acid and 4-bromobutyric acid, glycidol, glycidyl trimethylammonium chloride, and ethylene oxide. Particularly preferred modifying agents which include glycidol, and 2-bromoethanol.
Preferred fat binding polymers, copolymers or salts thereof in accordance with the invention are described in Examples 1-98.
Even more preferred fat binding polymers, copolymers (and/or salts thereof) of the invention comprises at least one repeat unit or a combination of repeat units selected from the following group of repeat unit formulas, or combinations of repeat unit formulas. 
Particularly preferred fat binding polymers, copolymers (and/or salts thereof) of the invention comprise the following:
A polymer of Formula II wherein: R1=H, R2=H, R5=CH3, m=1, p=about 114 and wherein the resulting polymer may be expressed as Poly((3-acrylamidopropyl)trimethylammonium chloride-co-O-acryloyl-Oxe2x80x2-methylpolyethyleneglycol 5000). Preferably, such polymer contains 11 wt % of the PEG-containing monomer;
A polymer of Formula III wherein R1=H, R2=H, R4=C12H25, R5=CH3 and wherein the resulting polymer may be expressed as Poly(3-methyl-1-vinylimidazolium chloride-co-acrylamide-co-dodecyl acrylamide). Even more preferably, such polymer has a monomer mole ratio of 35/70/5;
A polymer of Formula IV wherein R1=H, R2=H, R3=H, R4=C6H5(phenyl),m=1 and wherein the resulting polymer may be expressed as Poly((3-acrylamidopropyl)trimethylammonium chloride-co-acrylamide-co-N-phenylacrylamide). Even more preferably, such polymer has a Mol % monomer composition of 25/70/5;
A polymer of Formula V wherein R1=H, R2=H, R3=H, R4=C18H37, R5=CH3,m=1 and wherein the resulting polymer may be expressed as Poly((3-acrylamidopropyl)trimethylammonium chloride-co-acrylamide-co-N-methyl-N-octadecylacrylamide). Even more preferably such polymer has a Mol % monomer composition of 25/70/5;
The polymer of Formula VI which may be expressed as Poly(N,N-diallyl-N,N-di(2,3-dihydroxypropyl)ammonium chloride);
The polymer of Formula VII wherein R5=methyl and wherein such polymer may be expressed as Poly(N,N-diallyl-N-methyl-N-(2,3-dihydroxypropyl)ammonium chloride);
The polymer of Formula VIII which may be expressed as Poly(N,N-di(2,3-dihydroxypropyl)allylamine)hydrochloride;
A polymer of Formula IX wherein, R5=H, R6=H, R7=CH3, R8=CH3 and wherein such polymer may be expressed as Poly(N-(3-dimethylaminopropyl)maleimide-co-ethylene)hydrochloride;
A Polymer of Formula X wherein R5=H, R6=CH3, X=tartrate, and wherein such polymer may be expressed as Poly(N-methyl-N,N-diallylammonium)tartrate.
In addition, another particularly preferred polymer of the invention may be expressed as Polyethyleneimine 80% ethoxylated, the structure of which is understood in the art. Exemplative synthetic schemes for each of the preferred and particularly preferred polymers of the invention may be found in the Examples and particularly in Examples.
In another embodiment, the fat-binding polymer can have a lipase inhibitor covalently bound to the polymer as described in PCT/US99/00195. In a further embodiment, the fat-binding polymer can be administered in combination with a lipase inhibitor which is covalently bound to a polymer as described in PCT/US99/00195, the entire content of which is incorporated herein by reference.
As used herein, the terms xe2x80x9ctherapeutically effective amountxe2x80x9d and xe2x80x9ctherapeutic amountxe2x80x9d are synonymous. The terms refer to an amount which is sufficient to treat obesity, reduce the absorption of fat or treat hypertriglyceridemia. The dosage of fat-binding polymer administered to the patient will vary depending among other things on the weight of the patient and the general health of the patient. The dosage can be determined with regard to established medical practice. The amount of fat-binding polymer administered can be in the range of from about 0.01 mg/kg of body weight/day to about 1 g/kg of body weight/day. The amount of lipase inhibitor which can be administered in combination with the fat-binding polymers of the invention can be determined with regard to accepted medical practice (e.g. the Physicians Desk Reference).
As disclosed above, in a preferred embodiment, the preferred and particularly preferred fat-binding polymers in accordance with the invention are administered in combination with a lipase inhibitor, as described herein. The term xe2x80x9cin combinationxe2x80x9d in this context includes both simultaneous or sequential administration (either type of compound first) of the fat-binding polymer and lipase inhibitor. The fat-binding polymer and lipase inhibitor, when used in combination, can be employed together in the same dosage form or in separate dosage forms taken at the same time or within a time period, wherein both the fat-binding polymer and lipase inhibitor are present in a therapeutically effective amount.
The fat-binding polymers of the invention can be formulated using conventional inert pharmaceutical adjuvant materials into dosage forms which are suitable for oral administration. The oral dosage forms include tablets, capsules, suspension, solutions, and the like. The identity of the inert adjuvant materials which are used in formulating the fat-binding polymers of the invention will be immediately apparent to persons skilled in the art. These adjuvant materials, either inorganic or organic in nature, include, for example, gelatin, albumin, lactose, starch, magnesium stearate, preservatives (stabilizers), melting agents, emulsifying agents, salts, and buffers.
In patients with hypertriglyceridemia it is to be understood that the patient does not necessarily suffer from hypercholesterolemia.